Elsevier

Molecular Metabolism

Volume 4, Issue 9, September 2015, Pages 643-651
Molecular Metabolism

Brief communication
The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice

https://doi.org/10.1016/j.molmet.2015.06.002Get rights and content
Under a Creative Commons license
open access

Highlights

  • The beneficial effects of a novel complex I inhibitor, R419, were examined in skeletal muscle AMPK deficient obese mice.

  • R419 improves skeletal muscle insulin sensitivity in obese mice.

  • R419 improves exercise capacity in obese mice via an AMPK dependent pathway.

  • These findings suggest that R419 may have therapeutic importance in improving exercise capacity and skeletal muscle insulin sensitivity.

Abstract

Objective

Skeletal muscle AMP-activated protein kinase (AMPK) is important for regulating glucose homeostasis, mitochondrial content and exercise capacity. R419 is a mitochondrial complex-I inhibitor that has recently been shown to acutely activate AMPK in myotubes. Our main objective was to examine whether R419 treatment improves insulin sensitivity and exercise capacity in obese insulin resistant mice and whether skeletal muscle AMPK was important for mediating potential effects.

Methods

Glucose homeostasis, insulin sensitivity, exercise capacity, and electron transport chain content/activity were examined in wildtype (WT) and AMPK β1β2 muscle-specific null (AMPK-MKO) mice fed a high-fat diet (HFD) with or without R419 supplementation.

Results

There was no change in weight gain, adiposity, glucose tolerance or insulin sensitivity between HFD-fed WT and AMPK-MKO mice. In both HFD-fed WT and AMPK-MKO mice, R419 enhanced insulin tolerance, insulin-stimulated glucose disposal, skeletal muscle 2-deoxyglucose uptake, Akt phosphorylation and glucose transporter 4 (GLUT4) content independently of alterations in body mass. In WT, but not AMPK-MKO mice, R419 improved treadmill running capacity. Treatment with R419 increased muscle electron transport chain content and activity in WT mice; effects which were blunted in AMPK-MKO mice.

Conclusions

Treatment of obese mice with R419 improved skeletal muscle insulin sensitivity through a mechanism that is independent of skeletal muscle AMPK. R419 also increases exercise capacity and improves mitochondrial function in obese WT mice; effects that are diminished in the absence of skeletal muscle AMPK. These findings suggest that R419 may be a promising therapy for improving whole-body glucose homeostasis and exercise capacity.

Keywords

Exercise-mimetic
Mitochondrial
Diabetes
Obesity
AMPK
Complex-I
R419

Abbreviations

2-DG
2-deoxyglucose
ACC
acetyl-CoA carboxylase
AICAR
5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside
AMPK
AMP-activated protein kinase
AMPK-MKO
skeletal muscle-specific AMPK β1β2 floxed Cre-
AUC
area under the curve
COX
cytochrome c oxidase
CT
computed tomography
EDL
extensor digitorum longus
HFD
high-fat diet (45% kcal fat)
GDR
glucose disposal rate
GIR
glucose infusion rate
GLUT4
glucose transporter 4
HGO
hepatic glucose output
OXPHOS
proteins involved in oxidative phosphorylation (electron transport chain)
R419
N-(1-(4-cyanobenzyl) piperidin-4-yl)-6-(4-(4-methoxybenzoyl) piperidine-1-carbonyl
Tbp
TATA-binding protein
TA
tibialis anterior
WT
wildtype

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